Current Diagnosis & Treatment of Pain, 1st Edition

16. Sickle Cell Disease

Eufemia Jacob PhD, RN

Elizabeth Ely PhD, RN

Sickle cell disease (SCD) is a group of conditions characterized by production of abnormal hemoglobin, with clinical manifestations that vary by genotype and age. The first description of sickle cell disease was made in 1910 by Dr. James B. Herrick who noted that a patient of his from the West Indies had an anemia characterized by unusual red blood cells that were “sickle”-shaped. Sick-ling of the red blood cells was demonstrated to be related to low oxygen, and the low oxygen altered the structure of the hemoglobin in the molecule. Sequencing the DNA of the sickle hemoglobin showed that a glutamic acid at position 6 of the β-globin chain was replaced by a valine. Using the known information about amino acids and the codons that coded for them made it possible to predict the mutation in sickle cell disease. This made sickle cell disease the first genetic disorder whose molecular basis was known.

Essentials of Diagnosis

  • Identified through newborn screening in 48 states.
  • Confirmatory testing by serum electrophoresis.
  • Because this is a genetic disorder, the phenotype (disease expression) is extremely variable, though the genotype can somewhat predict disease severity.
  • There are four principal genotypes: SCD-SS, SCD-SC, SCD-β°-thalassemia, and SCD-β+-thalassemia.
  • Hallmark symptoms of the disease are anemia and vaso-occlusive pain.
  • Early diagnosis is essential so that prophylaxis with penicillin can be started by 3 months of age.
  • Pain in SCD often begins as dactylitis (hand/foot syndrome), starting at 6 months of age for some children and continues as the most common disease manifestation throughout life.

General Considerations

SCD is a chronic disease affecting 1 in 400 black Americans; 1 in 12 is a carrier of the trait. In infants and young children, infection is of greatest concern because it can lead to sepsis, splenic sequestration, silent infarct in the brain or overt stroke, acute chest syndrome, and vaso-occlusive pain. As children reach adolescence and adulthood, risks of stroke, renal disease, pulmonary hypertension, and leg ulcers increase, and the vaso-occlusive pain can become debilitating and chronic (eg, avascular necrosis of the hip or shoulder).

Pathogenesis

Following are the four principal genotypes:

  1. SCD-SSis the most common and most severe genotype.
  2. SCD-SCgenotype generally causes less severe disease, though patients with this genotype are at higher risk for sickle retinopathy than those with SCD-SS.
  3. SCD-β° thalassemiais considered to cause disease as severe as SCD-SS.
  4. SCD-β+ thalassemiacauses a milder form of the disease.

Compared with normal red blood cells, which survive 120 days in the bloodstream, sickle hemoglobin S, C,β°-thalassemia, and β+-thalassemia, which replace hemoglobin A in SCD, survive only 10 to 30 days, resulting in anemia, reticulocytopenia, and increased workload for the spleen. Under conditions of lower oxygen tension (eg, fever, reactive airway disease, dehydration, stress), hemoglobin becomes elongated in shape “sickled” and clumps together in the microvasculature causing oxygen depletion to tissues and eventual necrosis. The sickling can occur anywhere in the body causing organ damage as well as pain.

Prevention

Early diagnosis is essential so caregivers may be taught how to monitor infants and young children for known complications. Children should be examined in a specialty clinic at least 2 to 3 times a year.

All children 3 to 4 months through 5 years of age are given penicillin prophylaxis (penicillin VK 125 mg twice a day, increased to 250 mg, twice a day at 3-5 years of age). Parents and caregivers of infants with SCD should

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be taught to palpate the spleen on a daily basis and note any changes in size. Also, caregivers need to know that a fever of 101°F or above is an emergency and needs immediate attention.

Immunizations need to be up-to-date. All patients with SCD need the influenza vaccine yearly beginning in infancy as well as pneumoccocal immunization with PCV7 (Prevnar) in infancy and PPV23 (Pneumovax) at 24 months.

While many complications are difficult to prevent, some basic health maintenance behaviors are important to adopt at a young age and include the following:

  1. Decreasing exposure to persons with respiratory in fections or illness.
  2. Washing hands meticulously.
  3. Identifying reactive airway disease and treating it aggressively.
  4. Avoiding extreme temperatures and dressing appropriately.
  5. Drinking enough fluids to avoid dehydration.
  6. Getting adequate sleep to decrease fatigue.
  7. Minimizing psychological stressors.
  8. Eating a balanced nutritional diet with folic acid and zinc supplementation.
  9. Monitoring growth and development closely, both for growth delay and neurocognitive development.
  10. Performing transcranial Doppler (TCD) screening, starting at 2-3 years of age for patients with SCD-SS genotype. TCD velocity >200 cm/sec is an abnormal finding. Continue screening yearly.
  11. Tracking school attendance and performance.
  12. Avoiding high altitudes, such as mountain climbing and flying in a depressurized airplane.
  13. Avoiding reptiles due to increased risk of exposure to Salmonella.

Preventing vaso-occlusive pain is difficult because there are few identifiable precipitating events. Viral illness or bacterial infection, dehydration, stress, changes in the weather, menses, and fatigue are all possible causes of vaso-occlusive pain. Perhaps the most frustrating aspect of dealing with vaso-occlusive pain is its variability both in occurrence and morbidity, even when the patient is carefully adhering to guidelines for prevention. The variability in the frequency of pain episodes is generally related to the hemoglobin phenotype, level of fetal hemoglobin, concurrent illness, physical condition, psychological factors, and social variables. Chronic pain syndromes may develop in patients with chronic damage to bones, nerves, and other tissues with inflammation and fibrosis.

Clinical Findings

The clinical manifestations of SCD include hemolytic anemia, increased frequency and severity of infections, tissue and organ damage, and recurrent painful episodes caused by ischemia. Hemolytic anemia causes moderate to severe decrease in the hemoglobin level, increased reticulocytes produced in the bone marrow, jaundice from increased bilirubin, and increased lactic dehydrogenase.

Bacterial infections cause significant morbidity and mortality, and the early loss of splenic function increases the risk of severe infections, such as meningitis, pneumonia, sepsis, osteomyelitis, and salmonellosis.

Tissue and organ damage, reduced delivery of oxygen to tissues and organs that result from increased blood viscosity, adherence of blood cells to vascular walls, and activation of the coagulation system may contribute to such complications as vascular occlusion, infarctions, is-chemic necrosis, and hemorrhage. Damage may occur to any organ in the body, including the brain, lungs, liver, spleen, kidneys, bones, and eyes.

Recurrent painful episodes are caused by ischemia due to decreased blood flow, inflammation from bone marrow, and muscle necrosis.

The reason for most emergency department visits and hospitalizations is management of pain associated with an acute vaso-occlusive painful episode, with the average length of stay lasting between 5 and 10 days.

Ballas SK. Sickle cell anaemia: progress in pathogenesis and treatment. Drugs. 2002;62:1143..

Benjamin LJ et al. Guideline for the Management of Acute and Chronic Pain in Sickle Cell Disease. Glenview, IL: American Pain Society; 1999.

Dampier C et al. Vaso-occlusion in children with sickle cell disease: clinical characteristics and biologic correlates. J Pediatr Hematol Oncol. 2004;26:785..

Taylor C et al. Clinical presentation of acute chest syndrome in sickle cell disease. Postgrad Med J. 2004;80:346..

Pain Assessment

Because of the unpredictable, recurrent, intense, and frequently persistent pain experiences that occur during the lifetime of persons with SCD, the American Pain Society recommends two categories of assessment: rapid pain assessment and comprehensive pain assessment.

The goal of rapid pain assessment during a painful episode is immediate treatment. Pain assessment is relatively brief and easy to perform (Table 16-1). It is important to assess not only pain intensity, using an age-appropriate scale, but also other dimensions such as pain location and pain quality. Measurements need to be repeated over time and supplemented by physical findings, laboratory data, and diagnostic procedures.

Table 16-1. Rapid Pain Assessment during a Painful Episode.

· Use developmentally and cognitively appropriate pain measurew
- FLACC Pain Rating Scale (0 to 2 years)
- CHEOPS Observational Rating Scale (0 to 2 years)
- Faces (Wong-Baker, Bieri, Oucher) Pain Rating Scale (3 to 7 years)
- Adolescent Pediatric Pain Scale (8 years and older)
- 0 to 10 Numerical Rating Scale (8 years and older; adults)
- McGill Pain Questionnaire (adults)

· Assess dimensions of sickle cell pain
-Intensity: varies from mild to excruciating both within and between episodes
-Location: the most frequent sites affected are the abdomen, back, chest, and joints
-Quality: described as deep-seated, boring, or like a toothache
-Onset: consider any precipitating events to inform potential prevention strategies
-Duration: severity of pain varies from mild transient attacks of 5-10 minutes in a wrist to a more severe,
generalized pains lasting days or weeks and requiring hospital management
-Variations/rhythms: painful episodes develop most frequently in late afternoon and during the night
-Frequency: painful episodes are most frequent between 19 to 39 years of age and increase significantly in
males 15 to 25 years of age; painful crises decrease after age 30 and are rare after age 40; in persons over
20 years of age, mortality is highest in those with the most frequent painful episodes.

· Frequency of assessment
- Before intervention
- At peak effect
- At frequent intervals (10-15 minutes) until adequacy and duration's effects are determined (type and route
dependent)

· Document interventions and response to facilitate tracking of effectiveness as well as for evaluation of
interventions in a timely manner

SOURCE: Data from Benjamin LJ et al. Guideline for the Management of Acute and Chronic Pain in Sickle Cell Disease.
Glenview, IL: American Pain Society; 1999.

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Pain occurs at any location where nociceptors are present. It may be localized, involve several areas, be diffuse, or be migratory. Pains are generally bilateral and symmetric and may move from one joint to another. Tenderness or pressure over affected sites is common. Pain location surface area may decrease dramatically even when pain intensity does not change. Figure 16-1 is an example of body outline drawings that illustrate no change in pain intensity ratings from day 1 to day 3, and a dramatic change in the number and spatial distribution of painful body areas.

The assessment of pain quality may suggest the type of tissue involvement. Pain perceived as constant, gnawing, aching, sharp, or throbbing may be well localized and may involve the musculoskeletal system. Pain perceived as constant, dull, deep, or squeezing, and which is often accompanied by nausea, vomiting, hypertension, tachycardia, tachypnea, and diaphoresis may result from the activation of nociceptors in the thoracic and abdominal viscera. Pain perceived as severe, constant, dull ache, with superimposed paroxysms of burning, shooting, or electric shocklike sensations may result from ischemia, necrosis, inflammation, or infarction to the central or peripheral neural tissues. If these types of pain persist, neuropathic pain may develop and may be more difficult to treat.

  1. Comprehensive pain assessmentoccurs at the time of admission and at least once or twice a year, and more frequently as needed. The goal of comprehensive clinical assessment is treatment planning that involves the patient, family, and health care team.

Multidimensional assessment is summarized in Table 16-2 and includes physiologic, sensory, affective, cognitive, behavioral, and sociocultural factors. A multidisciplinary approach should include hematologists, pain teams, psychologists, physiotherapists, nurses, pharmacists, and others as warranted.

Differential Diagnosis

During the initial rapid pain assessment, it is vital to detect medical complications requiring specific therapy. The cause of the pain dictates the therapy. Therefore, asking the patient what type of pain he or she typically experiences during an episode is helpful. If the pain episode is typically what the patient experiences, the patient is treated for a routine pain episode. If

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the pain is not typical, the cause of pain (Table 16-3) needs to be determined and may include any of the following:

  1. Infection
  2. Dehydration
  3. Acute chest syndrome versus pneumonia (fever, tachypnea, chest pain, hypoxia, chest signs)
  4. Severe anemia
  5. Cholecystitis
  6. Splenic enlargement
  7. Abdominal crisis
  8. Neurologic events (cerebral infarct, cerebral hemorrhage, transient ischemic attack, seizure)
  9. Priapism.
 

Figure 16-1. Patient markings on body outline diagram of location of pain on days 1, 2, and 3. Pain intensity ratings did not change (9.0 centimeter on the word graphic rating scale). However, the surface area and spatial distribution of the pain changed dramatically. (Adapted, with permission, from Savedra MC et al. Pain location: validity and reliability of body outline markings by hospitalized children and adolescents. Res Nurs Health. 1989; 12:307.)

Table 16-2. comprehensive clinical assessment of pain.

Pxhysical factors
Blood pressure
Heart rate
respiration
Oxygen saturation level
Chest and abdominal findings
Pain sites, tenderness, warmth, swelling
Laboratory data
Radiology data

Dimensions of pain
Intensity
0 to 10 numerical rating scale (mild, 0-3; moderate, 4-6;
   severe, 7-10)
Location and quality
Precipitating factors

Demographic and psychosocial factors
Age and developmental level
Gender
Family factors
Cultural factors
Adaptation to sickle cell disease
Coping styles
Cognitive abilities
Mood
Level of distress

Impact of pain on functioning
Self-care
School/work
social activities
relationships
pattern ability(adults)

SOURCE: Data from Benjamin LJ et al. Guideline for the Management of Acute and Chronic Pain in Sickle Cell Disease.
Glenview, IL: American Pain Society; 1999.

Table 16-3. Complications of Sickle Cell Disease and Their Management.

Complications

Diagnosis/clinical findings

Related information

Management

Acute chest
   syndrome

Pulmonary infiltrates on
   chest radiograph
Chest pain
Fever
Reduced oxygen saturation
Decreased heart rate and
   respiratory rate

Bacterial or viral infection
Pulmonary fat embolism
Pulmonary edema
Microvascular/macrovascular
   lung infarction

Cautious administration of
   analgesia and IV
   hydration
Oxygen supplementation
Empiric antibiotics while
   awaiting culture results
Transfusion in presence of
   multilobar involvement
   with anemia, rapidly
   progressive, and
   respiratory failure
Exchange transfusion if
   hemoglobin SS
   concentration needs to
   be reduced to less than
   30%

Aplastic crisis

Transient arrest in
   erythropoiesis with
   secondary decreased HgB
   concentrations,
   decreased 1 g/dL from
   baseline

Infection with parvovirus
   B19, and sometimes
   Streptococcus
   pneumoniae, Salmonella
,
   or Epstein-Barr virus

Transfusions, which can be
   intermittently necessary
   for several weeks
IV immune globulin may be
   administered if patient
   has refractory parvovirus
   B19 infection

Splenic se
   questration
Splenic enlargement

Significant drop in
   hemoglobin, decreased
   1 g/dL from baseline

Vaso-occlusion in the
   spleen which causes a
   marked decrease in
   hemoglobin
   concentration

Exchange transfusion
If recurrent, splenectomy
   may be indicated after
   an acute episode

Silent infarct
   or overt
   stroke

CT scan to evaluate for
   hemorrhage followed by
   MRI; MRA in presence of
   intracranial hemorrhage
TCD flow study to detect
   subclinical neurologic
   disease/silent infarct
Screening with TCD should
   be done by 3 years of age
   or younger for SCD-SS
   genotype and continued
   yearly

The following risk factors
   have been identified:
   previous transient
   ischemic attack, low
   steady-state hemoglobin,
   increased steady-state
   leukocyte count, acute
   chest syndrome within
   the previous 2 weeks,
   elevated systolic blood
   pressure.
Intracranial hemorrhage
   has a very high
   immediate mortality;
   peak incidence between
   ages 20 and 29; presents
   with headache,
   increased intracranial
   pressure, altered level of
   consciousness, and focal
   neurologic deficits

Use of exchange
   transfusion to keep HgbS
   concentration below 30%
   during an acute stroke
May be prevented with
   transfusions in children
However, prophylactic
   transfusion for strokes in
   adults has not been
   studied and is generally
   not recommended

Hypertension

Increased blood pressure

May reflect underlying
   renal disease

β-Blockers and calcium
   channel blockers are the
   mainstays of therapy
ACE inhibitors may be
   useful if patient has
   proteinuria
Diuretics are used with
   caution so that
   dehydration and sickling
   are not precipitated

Gallstones

Abdominal ultrasound for
   diagnosis
Abdominal pain, icteric
   sclera often present

Increased bilirubin
   production from chronic
   hemolysis increases risk
   of gallstones

Surgical removal

Renal

Renal ultrasound,
   cystoscopy, and culture
Hematuria, proteinuria,
   nocturnal enuresis

Painless hematuria;
   proteinuria is present in
   25% of adults with sickle
   cell disease; can progress
   to nephrotic syndrome
   from membranoproliferative
   glomerulo
   nephritis

Aggressive hydration to
   keep urine flow high,
   alkalinization of urine
   and bedrest
Sickle cell disease is not a
   contraindication for
   hemodialysis or renal
   transplant

Avascular
   necrosis

MRI of affected joint
Joint pain, change in gait if
   hip is affected

Peak incidence between 25
   and 35 years of age

Joint replacement may be
   necessary to treat pain
   and improve function.
   Hip coring to increase
   blood flow and relieve
   symptoms. Physical
   therapy aimed at
   increasing joint mobility
   and strength.

Priapism

Failure of an erection to
   subside spontaneously

Between 30 and 50% of
   male patients report at
   least one episode in their
   lifetime

May subside spontaneously
Failure of an erection to
   subside after several
   hours is an urologic
   emergency
Management includes
   aggressive IV hydration,
   opioids for pain relief,
   and exchange
   transfusion if necessary
May require penile
   aspiration

CT, computed tomography; MRI, magnetic resonance imaging; MRA, magnetic resonance angiography; TCD,
transcranial Doppler; ACE, angiotensin-converting enzyme.

Table 16-4. Diagnostic Indications.

Indications

Diagnostic procedure

Febrile, breathless, tachypnea, chest pain, chest signs,
   decreased oxygen saturation levels

Chest radiograph

Oxygen saturation less than 95%; unexpected
   drowsiness, lethargy

Continuous oxygen saturation monitoring Arterial blood gases

High amylase, increased jaundice, abdominal pain

LFTs

Hemoglobin value normal or lower or falling

CBC with reticulocytes

Abnormal LFTs, abdominal pain, splenomegaly

Ultrasound of abdomen

Febrile, rigors, hypotensive

Blood and urine cultures

Reticulocytopenia

Parvovirus B19 serology

Seizure, transient ischemic attack, stroke, severe
   headache, weakness

MRI/MRA

History of trauma, persistent unexplained swelling

Limb radiographs

LFT, liver function tests; CBC, complete blood count; CT, computed tomography; MRI, magnetic resonance imaging.

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Investigations should be directed toward specific clinical problems (Table 16-4).

Benjamin LJ et al. Guideline for the Management of Acute and Chronic Pain in Sickle Cell Disease. Glen view, IL: American Pain Society; 1999.

Jacob E et al. Changes in intensity, location, and quality of vaso-occlusive pain in children with sickle cell disease. Pain. 2003;102:187..

Moritani T et al. Sickle cell cerebrovascular disease: usual and unusual findings on MR imaging and MR angiography. Clin Imaging. 2004;28:173..

Taylor C et al. Clinical presentation of acute chest syndrome in sickle cell disease. Postgrad Med J. 2004;80:346..

Zar HJ. Etiology of sickle cell chest. Pediatr Pulmonol Suppl. 2004;26:188..

Complications

The severity of symptoms and the occurrence of the various complications caused by SCD (Table 16-3) are variable. Morbidity and mortality of SCD begins in infancy and continues through middle age, the current lifespan for persons with SCD. Persons with the SCD-SS genotype are at greatest risk for most of the complications and for greatest severity of pain. However, clinical phenotypes are not clearly understood and anyone with any form of the disease can experience complications and risks of this disease.

SCD has the potential for multisystem involvement during the patient's lifetime because the sickled hemoglobin can cause decreased blood flow in the mi-crovasculature of any area of the body (Table 16-3).

Treatment of Pain

The lack of consistency in health care professionals in the emergency department and acute care units often results in different approaches to pain management with each visit. According to the American Pain Society, severe pain is a medical emergency and should be treated promptly and aggressively until the patient indicates that the pain is tolerable. Persons who seek medical attention at an emergency department usually have exhausted all homecare options or outpatient therapy. The selection of analgesics and loading dose is based on prior history and current assessment. The patient should be asked what medication and dosage are usually given, what side effects have been experienced in the past, what medication is usually taken at home, and what medication has been taken since the onset of present pain. The patient may be receiving long-term opioid therapy at home, and therefore, some degree of tolerance may have developed. A different potent opioid or a larger dose of the same medication may be indicated. Because mixed opioid-agonist-antagonists (eg, pentazocine, nalbuphine, butorphanol) may precipitate withdrawal syndromes, these should be avoided if the patient was taking opioids chronically at home.

To facilitate initial pain management, patients can be issued cards (serving as a “passport”) that they carry with them at all times (Figure 16-2). The diagnosis, baseline

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hematologic data, and usual analgesic requirements should be specified on these cards. The name and phone number of the primary care provider or hematologist, or both, should also be included on the card in case emergency department physicians have questions or need consultation. An ideal goal is to have analgesics be given within 30 minutes of entering the emergency department, and effective analgesia should be achieved by 60 minutes. Pain, respiratory rate, and sedation should be assessed every 20 minutes until pain is well controlled. Once pain is controlled, the underlying cause should be assessed more comprehensively; carefully investigate those that are not typical pain for patient.

 

Figure 16-2. Example of a “passport” card with individual information about patient's diagnosis, baseline hematologic data, and usual analgesic requirements specified in the back, as well as name and phone number of the primary care provider or hematologist.

Admission to the hospital is indicated under the following circumstances:

  1. The patient is not pain free after 8 hours of outpatient treatment.
  2. The patient returns for additional therapy within 48 hours of previous inpatient or outpatient treatment of a pain episode.
  3. The patient has a pain episode plus any one of the following: infection, significant hypoxia or acidosis, pregnancy, cardiac decompensation, priapism, thromboembolic events in lungs and central nervous system or bone infarctions, aplastic or hyper-hemolytic crisis (fall in hemoglobin > 1 g/dL over baseline), or hepatic syndromes or cholecystitis.

In the step-wise approach to vaso-occlusive disorders, pain management is warranted. Nonsteroidal anti-inflammatory drugs (NSAIDs) and weak opioids are used for mild pain, and opioids are added as needed for moderate to severe pain.

  1. NSAIDs and Acetaminophen

The management of mild to moderate pain includes the use of NSAIDs or acetaminophen (Table 16-5). NSAIDs are nonsedating and mostly given orally, except for ketorolac, which is also available parenterally. Parenteral ketorolac has been shown to have an equivalent analgesic action to morphine. NSAIDs and acetaminophen have ceiling doses, beyond which no increased analgesia is achieved with increasing doses. Persons with SCD have varying degrees of hepatic impairment, and therefore, acetaminophen may be contraindicated. Also, for persons with gastritis, peptic ulcers, coagulopathies, and renal

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failure, NSAIDs are contraindicated. Clinicians should monitor doses and frequency of treatment. Urinalysis and biochemical measures of renal function should be monitored every 3 to 6 months if NSAIDs are frequently used.

Table 16-5. Nonopioids used for mild pain.

Drug

Dosagea

Acetaminophen

10-15 mg/kg q4h; 650 mg q4h PO

Ibuprofen

10 mg/kg q6-8; 400-800 mg q4h

Ketoprofen

0.5 mg/kg q6h; 25-75 mg q6-8h

Naproxen

5-7 mg/kg q8-12h; 500 mg
   initially, then 250 mg q6-8h

Ketorolac

0.5mg/kgIVq8h;30mgIV
   initially, then 15-30 mg q6h
   max 5 days or 120 mg/day or 10
   mg q4-6h PO; max 40 mg/d

aBased on weight of 50 kg or more.
SOURCES: Data from Taketomo C et al. Pediatric Dosage
Handbook. Hudson, Ohio: Lexi-Comp; 2004; Benjamin LJ
et al. Guideline for the Management of Acute and Chronic
Pain in Sickle Cell Disease.
 Glenview, IL: American Pain
Society; 1999.

  1. Opioids

The American Pain Society recommends the use of opioid or opioid formulations with short duration of action for pain lasting less than 24 hours, for rescue dosing with breakthrough pain, or until the sustained-release opioid preparation reaches steady-state levels. For sickle cell-related pain requiring several days to resolve, sustained-release opioid preparations are more convenient and provide more consistent analgesia. Opioids such as codeine and oxycodone are used orally for mild or moderate pain (Table 16-6). They are often used in combination with nonopioid analgesics (Table 16-7), such as acetaminophen or aspirin. However, the presence of acetaminophen or aspirin limits the amount of opioid that can be administered using these combinations (Table 16-8).

  1. Titration—

The starting dose of opioids for severe sickle cell pain usually depends on pain intensity, the patient's size, and their previous opioid experience. An initial loading dose equivalent to 5-10 mg of morphine (0.1-0.2 mg/kg for children) is recommended (Table 16-9). An additional smaller rescue dose of 2.5-5.0 mg (0.05-0.10 mg/kg for children) every 30-60 minutes may be given if needed to achieve or maintain adequate analgesia. Ketorolac (15-30 mg IV) or ibuprofen (600 mg PO; 10 mg/kg in children) every 6 hours is added if the patient has no history of renal disease, peptic ulcer disease, or other contraindications.

Table 16-6. Opioids for Moderate to Severe Pain.

Drug

Dosage

Codeine

0.5-1 mg/kg q3-4h PO
15-60 mg q3-6h (50 kg or more)

Morphine
   (MSIR)

0.3 mg/kg q3-4h PO
10-30 mg q3-4h PO (50 kg or more)

Oxymorphone

0.5-1.5 mg q6h IV

Hydrocodone/
   oxycodone

0.15-0.20 mg/kg q3-4h PO
10 mg q3-4h PO (50 kg or more)

SOURCES: Data from Taketomo C et al. Pediatric Dosage
Handbook. Hudson, Ohio: Lexi-Comp; 2004; Benjamin L
et al. Guideline for the Management of Acute and Chronic
Pain in Sickle Cell Disease.
 Glenview, IL: American Pain
Society; 1999.

Response to therapy should be evaluated 15 to 30 minutes after each dose, and dosages should be titrated to relief. Relief is defined as a score of 2 or greater on a pain relief scale (0 = no relief, 1 = little relief, 2 = moderate relief, 3 = good relief, 4 = complete relief), or a 50% reduction from the upper end of the pain intensity scale. Significant relief has not been achieved if a patient rates 0 or 1 on the above pain relief scale. Titration should

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continue until adequate relief scores are achieved, or until side effects become problematic.

Table 16-7. Combination NSAID and Opioid Therapy for Mild to Moderate Pain.

Drug

Dosage

Hydrocodone +
   acetaminophen

0.6 mg/kg/d
Not to exceed 1.25 mg/dose in
   children younger than 2 years
   of age; 5 mg/dose for children
   2-12 years of age; or
   10 mg/dose for patients older
   than 12 years of age

Hydrocodone +
   ibuprofen

1-2 tablets q4-6h
Maximum 5 tablets per day

Oxycodone + acetaminophen

0.05-0.15 mg/kg/dose
   (oxycodone)
Maximum 5 mg q4-6h; 1-2
   tablets q4-6h

Codeine +
   acetaminophen

0.5-1 mg/kg/dose (codeine) q6h
15-60 mg q4-6h; usual 30 mg/
   dose codeine

SOURCES: Data from Taketomo C et al. Pediatric Dosage
Handbook. Hudson, Ohio: Lexi-Comp; 2004; Benjamin L
et al. Guideline for the Management of Acute and Chronic
Pain in Sickle Cell Disease.
 Glenview, IL: American Pain
Society; 1999.

Table 16-8. Available Opioid Combination Products.

Drug
combination

Dosage and formulation

Acetaminophen +
   codeine

Oral
300 mg of acetaminophen +
7.5 mg, 15 mg, 30 mg, or 60 mg
of codeine
Elixir 120 mg/5mL of
acetaminophen +12 mg/5 mL
of codeine

Acetaminophen +
   oxycodone

Oral
325,500, or 650 mg of
acetaminophen + 2.5,5.0,
7.5, or 10 mg of oxycodone
Elixir
325 mg/5 mL of
acetaminophen +5 mg/mL of
oxycodone

Aspirin +
   oxycodone

325 mg of aspirin + 2.25 or
   4.5 mg of oxycodone

Acetaminophen +
   hydrocodone

Oral
325,400,500,650, or 750 mg of
   acetaminophen +2.5,5.0,
7.5, or 10 mg of hydrocodone
Elixir
108 or 167 mg/5 mL of
acetaminophen + 2.5 mg/5 mL
of hydrocodone

Ibuprofen +
   hydrocodone

200 mg of ibuprofen + 7.5 mg
of hydrocodone

SOURCE: Data from Taketomo C, Hodding J, KrausD. Pediatric
Dosage Handbook. Hudson, Ohio: Lexi-Comp; 2004.

There may still be some patients who may request the use of meperidine. However, the patient needs to be informed that it is the least potent and shortest-acting of the synthetic opioids and the least effective in providing analgesia for severe pain. More importantly, it may increase the risk of seizures when administered long-term because of the excitatory effects of its metabolite, normeperidine, on the nervous system. Some authors have argued that the incidence of meperidine-associated seizures is extremely small (0.4% of patients; 0.06% of admissions) and the risk of seizures should not dissuade clinicians from using this drug. However, the American Pain Society recommends that meperidine be reserved for very brief treatment courses for patients who have reported and demonstrated its effectiveness, or who have allergies or uncorrectable intolerances to other opioids. Meperidine should not be used for longer than 48 hours or doses >600 mg/24 hours.

  1. Patient controlled analgesia—

For severe pain, in travenous administration with bolus dosing and continuous infusion using a patient controlled analgesia (PCA) device may be necessary. For titration using PCA, a loading dose is administered, then, one-third of the estimated 24-hour dosing is administered by continuous infusion (Table 16-9). The other two-thirds is administered by patient or nurse in divided doses per hour on demand, with every 5 to 10 minutes lockout intervals. This may be given every 5 minutes during the first 2 hours to relief, which is the titration phase. A reassessment must be made every 60 minutes to titrate the appropriateness of the interval and dose until adequate relief is achieved.

Approximately 25 to 50% of maintenance dose may be administered for breakthrough pain. PCA settings may be adjusted if the number of rescue doses is increasing and the intervals between doses are too long. Standard orders should provide naloxone and resuscitation equipment in proximity. PCA should be immediately stopped and the physician notified for oversedation and respiratory rate less than 8 breaths per minute. PCA use and degree of pain control should be evaluated frequently and at least every 24 hours. Orders should be rewritten every 48 hours.

  1. Weaning—

When the patient is no longer experiencing severe pain, the patient requiring more than 5 to 7 days of opioids should have tapering doses to avoid the physiologic symptoms of withdrawal (dysphoria, agitation, nasal congestion, piloerection, diarrhea, sweating, and seizures). Weaning schedules for PCA have not been systematically studied. In general, the continuous infusion rate is progressively reduced prior to discontinuation, while the patient can continue to use demand doses for analgesia. Doses of long-acting oral analgesics, such as sustained-release oral morphine, may be used to replace continuous infusion dosing. The demand doses can be subsequently reduced if analgesia remains adequate. Weaning should not occur if a patient continues to experience severe pain. A patient may be discharged with a morphine equivalent equianalgesic dose (see Table 16-9) obtained by converting the continuous infusionrates to equivalent oral analgesics.

  1. Adjuvant Medications

To increase the analgesic effect of opioids, reduce side effects of analgesics, or manage symptoms (eg, anxiety and depression) associated with sickle cell pain, adjuvant medications may be added to the pain management regimen (Table 16-10). Sedatives and anxiolytics are used in combination with a potent opioid. Sedatives and anxiolytics may mask the behavioral response to pain without providing analgesia when used alone; however, when they are used in combination with opioids, risk for increased sedation is higher. Since sedation precedes opioid-induced respiratory depression, sedation levels should be monitored, and the use of incentive spirometry every 1 to 2 hours is recommended. Dose of opioids may be adjusted, or caffeine or methylphenidate may be added to the regimen as needed. For pruritus, adjunct medications such as diphenhydramine, hydroxyzine, continuous low-dose naloxone infusion, or switching to other opioids, such as hydromorphone or fentanyl have been effective in some cases. The use of opioids increases the risk for constipation, which can be minimized or prevented with the use of a stool softener and an osmotic laxative.

Table 16-9. Guidelines for Morphine, Hydromorphone, Fentanyl for Moderate to Severe Pain.

Drug

Guidelines

Morphine

IV:
0.1-0.2 mg/kg/dose q2-4h
Usual maximum 15 mg/dose
5-20 mg/dose q2-6h; 10 mg/dose q4h prn (for persons weighing more than 50 kg)
PO:
0.2-0.5 mg/kg/dose q4-6h, (for persons weighing less than 50 kg)
0.3 to 0.6 mg/kg/dose q12h (controlled-release)
10-30 mg q4h prn; controlled-release 15-30 mg q8-12h (for persons weighing 50 kg)

Morphine (PCA)

Loading dose: 0.03 to 0.1 mg/kg
Push dose: 0.01-0.03 mg/kg
Basal rate: 0.03 mg/kg/h initially; continuous infusion: 0.025-2.6 mg/kg/h
Lockout interval: 6-8 minutes
Hourly maximum: 0.1 mg/kg/h to 6-8 mg/h, initially. For persons weighing more than
   50 kg, 0.8-10 mg/h, usual range up to 80 mg/h; increase as needed to an amount that
   would relieve the pain

Hydromorphone

PO:
0.03-0.08 mg/kg/dose q4-6h prn; maximum, 5 mg/dose
0.06-0.08 mg/kg q3-4h; 7.5 mg q3-4h (for persons weighing 50 kg or more)
IV: 0.015 mg/kg/dose q3-6h prn as needed
Older children and adults (PO, IV, IM, SQ):
1-6 mg/dose q3-4h prn; usual adult dose 2 mg/dose; 0.015-0.020 mg/kg q3-4h IV
1.5 mg q3-4h IV (for persons weighing 50 kg or more)

Hydromorphone
   (PCA)

Loading dose: 20 mcg/kg (max 1.5 mg)
Push dose: 5 mcg/kg/dose
Basal rate: 1.5 mcg/kg/h
Lockout interval: 6-8 minutes
Hourly maximum: 20 mcg/kg/h

Fentanyl

IV: 0.5-2 mcg/kg/dose; may repeat at 30-60 minute intervals
Adults: 25-50 mcg; may repeat 25 mcg at 5 minute intervals, 4-5 times if needed

Fentanyl (PCA)

Loading dose: 1 -2 mcg/kg
Push dose: 0.3-1 mcg/kg/dose
Basal rate: 0.1 -1 mcg/kg/h initially; titrate upward as needed
Lockout interval: 6-8 minutes
Hourly maximum: 1.25 mcg/kg/h

IV Morphine Equivalent Equianalgesic Conversions

1 mg IV morphine = 20 mg PO codeine

1 mg IV morphine = 3 mg PO morphine

1 mg IV morphine = 3 mg PO hydrocodone

1 mg IV morphine = 3 mg PO oxycodone

10 mg IV morphine = 1.5 hydromorphone

6.66 mg IV morphine = 1 mg hydromorphone

PCA, patient-controlled analgesia.
SOURCES: Data from Taketomo C, Hodding J, Kraus D. Pediatric Dosage Handbook. Hudson, Ohio: Lexi-Comp; 2004
Benjamin LJ et al. Guideline for the Management of Acute and Chronic Pain in Sickle Cell Disease. Glenview, IL: American
Pain Society; 1999.

Table 16-10. Adjuvant Medications.

· Antihistamines (eg, hydroxyzine, diphenhydramine)

· Tricyclic antidepressants (eg, amitriptyline,
imipramine)

· Benzodiazepines (eg, diazepam, lorazepam,
clonazepam)

· Antipsychotics (eg, thioridazine, haloperidol)

· Barbiturates (eg, phenobarbital)

· Anticonvulsants (eg, phenytoin, carbamazepine)

SOURCE: Data from Benjamin LJ et al. Guideline for the Management
of Acute and Chronic Pain in Sickle Cell Disease.

Glenview, IL: American Pain Society; 1999.

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  1. Nonpharmacologic Management

Although analgesic medications are the mainstay of pain management during acute painful episodes, the combination with the use of nonpharmacologic management strategies (Table 16-11) provide additive effects. Their use may increase the effects of analgesics or result in decreased use of pain medications.

Information about pain and treatments should be communicated to the patient and family as an integral part of ongoing treatment. Education about self-care strategies, positive coping strategies, strategies for communicating with health care providers, and the cards that patients can carry at all times (see Figure 16-2) should be provided. Health care providers need not only prepare the patient with the “passport” but also need to communicate with emergency department staff. For example, working with emergency department personnel to develop protocols and establish lines of communication when patients with SCD come to the emergency department.

Cognitive therapies may be used to enhance active coping skills, decrease negative or dysfunctional thinking patterns, and facilitate therapeutic changes in mood. Distraction is very effective and can be done by repeated and prepared inspirational or affirming phrases, singing, talking, doing mental calculations, visualizing images, or engaging in any mental activity that is fully absorbing. Hypnotherapy techniques include hypnosis, meditation, imagery, and relaxation. Acupuncture and acupressure applied by the fingers to trigger points or acupuncture sites are based on the belief that optimal health is directly connected to a balance of flow of the life force along energy pathways called meridians.

Table 16-11. Nonpharmacologic Management of Sickle Cell Pain.

Strategies

Examples

Psychological

      Distraction
 Imagery
 Education/teaching
 Hypnotherapy
 Psychotherapy

Behavioral

      Deep breathing
 Relaxation exercise
 Self-hypnosis
 Biofeedback
 Behavior modification

Physical

      Hydration
 Heat
 Massage
 Physical therapy
 TENS
 Acupuncture
 Acupressure

TENS, transcutaneous electrical nerve stimulation.
Adapted, with permission, from Benjamin LJ et al. Guideline
for the Management of Acute and Chronic Pain in Sickle Cell
Disease
. Glenview, IL: American Pain Society; 1999.

  1. Other Treatments

Hydroxyurea has been demonstrated to significantly reduce the annual rates of acute painful vaso-occlusive episodes and hospitalizations. However, many patients continue to have painful crises, and the response to hydroxyurea is difficult to predict. It is possible that some patients have problems with compliance. Close monitoring is required to prevent myelotoxicity, and there is a low risk for mutagenicity associated with long-term use. The beneficial effects of hydroxyurea may not be manifest for several months, and at least a 6-month trial is recommended. The most common side effect is myelo-suppression, which is dose-dependent and is usually transient but may be prolonged. Nausea, vomiting, and skin rashes have also been reported.

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Anie KA et al. Psychological therapies for sickle cell disease and pain. Cochrane Database Syst Rev. 2000;(3):CD001916..

Benjamin LJ et al. Guideline for the Management of Acute and Chronic Pain in Sickle Cell Disease. Glen view, IL: American Pain Society; 1999.

Benjamin LJ et al. Sickle cell anemia day hospital: an approach for the management of uncomplicated painful crises. Blood. 2000;95:1130..

Bodhise PB et al. Non-pharmacologic management of sickle cell pain. Hematology. 2004;9:235..

Claster S et al. Managing sickle cell disease. BMJ. 2003;327:1151..

Elander J et al. Pain management and symptoms of substance dependence among patients with sickle cell disease. Soc Sci Med. 2003;57:1683..

Maxwell K et al. Experiences of hospital care and treatment seeking for pain from sickle cell disease: qualitative study. BMJ. 1999;318:1585..

Nadvi SZ et al. Low frequency of meperidine-associated seizures in sickle cell disease. Clin Pediatr (Phila). 1999;38:459..

Sumoza A et al. Hydroxyurea (HU) for prevention of recurrent stroke in sickle cell anemia (SCA). Am J Hematol. 2002;71:161..

Barriers to Adequate Pain Management

Patients with SCD often delay seeking treatment for pain until pain is very severe and intolerable. They prefer to treat their pain at home overnight or over the weekend until the Hematology Clinic or Sickle Cell Clinic opens when their primary care hematologist is available. However, the severity of pain compels most patients to go to the emergency department. While the hematologist in the clinic is familiar with the patient's clinical profile and the complications of SCD, the physician in the emergency department is less focused on the special nature of SCD. In 50% of the patients, there are no objective signs of a painful crisis.

The delay in seeking treatment violates a major guiding principle in pain management, which is that prevention of pain is always better than treatment. Pain that is established and severe is often more difficult to control. When pain is untreated, sensory input from injured tissues reaches spinal cord neurons and may cause subsequent pain responses to be enhanced or amplified. Long-lasting changes in cells within spinal cord pain pathways may occur after a brief painful stimulus and may lead to the development of chronic and persistent pain conditions. Recent studies on pain emphasize a distinct neurochemistry of persistent pain, which is not merely a prolonged acute pain symptom of the disease. There are underlying physiologic mechanisms that lead to the persistence of pain if left untreated. Clinicians may, therefore, consider establishing an early intervention or prevention protocol that may be instituted in an emergency department, urgent care, or day hospital, for hydration and early aggressive pain management. Protocols for outpatient management in a day care center have been developed as an alternative to hospital admission. The use of day hospitals and outpatient management protocols have reduced unnecessary hospital admissions.

The use of opioids, whether inpatient or outpatient, is the mainstay of therapy for severe pain. A major barrier to the use of opioids for effective management of sickle cell pain is the confusion between opioid tolerance, physical dependence, and addiction. Tolerance and physical dependence are expected pharmacologic consequences of long-term opioid use. The first signs of tolerance are decreased duration of the action of medication and patients experience pain before the next scheduled dose of opioid. When tolerance develops, larger doses or shorter intervals between doses may be needed to achieve the same analgesic effect. Pain experts question whether tolerance to the analgesic effect of opioids is a significant clinical problem and suggest that requests for higher doses of drug may reflect increasing pain stimuli. Physical dependence develops when opioids are given for more than 5 to 7 days. Withdrawal symptoms, such as dysphoria, nasal congestion, diarrhea, nausea, vomiting, sweating, and seizures may occur when opioids are stopped without weaning. Doses should be tapered to avoid the physiologic symptoms of withdrawal.

Addiction is not physical dependence. Addiction is psychological dependence, which is a very complex phenomenon with genetic, psychological, and social components. The use of opioids for acute pain relief is not addiction, regardless of the dose or duration of time the opioids are administered. Fears related to addiction among patients, family, and health care providers are unwarranted and lead to inadequate treatment.

Addictive disease includes a pattern of compulsive drug-use behaviors characterized by a continued craving for an opioid. Patients with addictive disease have a need to use the opioid for effects other than pain relief. They do not have control over drug use, and they compulsively use drugs despite the harmful effects. The risk for the development of these behaviors in patients with SCD is not any higher than other groups of patients.

The diagnosis and treatment of addiction (see Chapter 7) requires a referral to an addiction medicine specialist. The management of patients with a history of substance abuse is particularly a difficult and challenging problem. For those patients in whom an addictive disorder is suspected, an appropriate referral to an addiction specialist for a complete evaluation, diagnosis, and treatment should be made, rather than imposing judgment and denying the patient adequate pain management.

Some patients whose pain is managed poorly will try to persuade the medical staff to give them more analgesic,

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engage in clock-watching, and request specific medications or dosages. These patients are often perceived as manipulative and demanding. Because patients with SCD have lifelong experiences with medications that work and do not work, they are very knowledgeable about the medications and doses that are effective. Therefore, their requests for specific medications and doses should be respected and not be interpreted as indications of drug-seeking behavior.

Iatrogenic pseudoaddiction may develop in patients who are given doses of opioids that are inadequate to relieve their pain or in patients whose doses are not tapered after a course of treatment. Pseudoaddiction or clock-watching behavior may be resolved by communicating with the patient to ensure accurate assessment, involving them in decisions about their pain management, and by administering adequate opioid doses.

Benjamin LJ et al. Guideline for the Management of Acute and Chronic Pain in Sickle Cell Disease. Glenview, IL: American Pain Society; 1999.

Elander J et al. Understanding the causes of problematic pain management in sickle cell disease: evidence that pseudoaddiction plays a more important role than genuine analgesic dependence. J Pain Symptom Manage. 2004;27:156..

Elander J et al. Pain management and symptoms of substance dependence among patients with sickle cell disease. Soc Sci Med. 2003;57:1683..

Kirsh KL et al. Abuse and addiction issues in medically ill patients with pain: attempts at clarification of terms and empirical study. Clin J Pain. 2002;18(4 Suppl):S52..

Prognosis

The prognosis of sickle cell disease usually refers to the likely outcome of the disease. Sickle cell chronic lung disease is a prime contributor to mortality in young adult patients with SCD, especially those with the SCD-SS genotype. The prognosis of SCD may include the duration and number of complications, prospects for recovery, survival rates, death rates, and other outcome possibilities in the overall prognosis of SCD. Such forecast issues are by their nature unpredictable.

The average lifespan of a patient with SCD is now in the forties and continues to rise due to improved treatment. Some patients suffer only mildly whereas others have severe complications. Among patients with SCD who were older than 20 years of age, those with more frequent pain episodes tended to die earlier than those with less frequent episodes. Increased frequency of pain episodes was associated with a low hemoglobin, low hematocrit, and low fetal hemoglobin levels. The number of pain episodes per year is a measure of clinical severity and correlates with early death in patients with SCD over the age of 20.

In 1984, bone marrow transplantation in a child with SCD produced the first reported cure of the disease. The transplantation was done to treat acute leukemia. The child's SCD was cured as a side event. The procedure nonetheless set the precedence for later transplantation efforts directed specifically at SCD.

Bakanay SM et al. Mortality in sickle cell patients on hydroxyurea therapy. Blood. 2005;105:545..

Chakrabarti S et al. Will developments in allogeneic transplantation influence treatment of adult patients with sickle cell disease? Biol Blood Marrow Transplant. 2004; 10:23..

Locatelli F et al; Eurocord Transplant Group. Related umbilical cord blood transplantation in patients with thalassemia and sickle cell disease. Blood.2003;101:2137..

Prasad R et al. Long-term outcome in patients with sickle cell disease and frequent vaso-occlusive crises. Am J Med Sci. 2003;325:107.http://www.scinfo.orgThe Sickle Cell Information Center at the Georgia Comprehensive Sickle Cell center at Emory University provides a monthly update on professional publications about sickle cell disease, new web sites that might be helpful, and conferences of interest for health care professionals and parents as well as educational products and services.

http://www.rhofed.com/sickle/index.htm This is the web site of the 10 Comprehensive Sickle Cell Disease Centers funded by the National Heart Lung and Blood Institute of the National Institutes of Health. The ongoing research and clinical care focus of these centers is listed along with links to other sites that provide educational resources on sickle cell disease.

http://www.nhlbi.nih.gov/health/prof/blood/sickle/index.htm At this web site, the fourth edition of The Management of Sickle Cell Disease can be viewed and downloaded.

http://www.is.dal.ca/~pedpain/ This site is dedicated to providing information about up-to-date pain research in children and provides links to web resources for children and families to help them cope with painful procedures and learn how best to tell others about pain.